inactivation of E-cadherin mediated cell - cell adhesion may play an important role in the complex process of prostate cancer metastasis. Down-regulation of E-cadherin expression correlates with high tumor grade and stage in human prostate cancers. In a small subset of patients we have shown that E-cadherin immunoreactivity is a predictor of biochemical recurrence in prostate cancer patients. However, the mechanism responsible for down-regulation of e- cadherin expression in prostate cancer cells is incompletely understood. Hypothesis: Loss of E-cadherin expression results in prostate cancer cells with increased metastatic potential. Accordingly, analysis of E- cadherin immunoreactivity will improve our ability to predict prostate cancer progression. Hypermethylation of 5' regulatory sequences is associated with loss of E-cadherin expression, and may be the molecular mechanism responsible for inactivation of E-cadherin expression in prostate cancer cells. Further, upregulation of E- cadherin expression with demethylating agents may inhibit prostate cancer progression. Specific aims: 1) Analyze E- cadherin expression in primary human prostate cancers. Use survival analysis and a Cox proportional Hazards model to show that E- cadherin expression is an independent predictor of disease free survival. 2) use genomic sequencing to show that hypermethylation of 5' regulatory sequences is associated with down-regulation of E-cadherin gene expression. 3) Determine the temporal relationship between: (a) inactivation of E-cadherine mediated cell - cell adhesion; (b)) the development of metastasis; and (c)) hypermethylation of 5' regulatory sequences of the E-cadherin gene in a transgenic mouse model of prostate cancer. 4) Determine whether E-cadherin expression can be restored in vivo using the demethylating agent 5-aza-2'-deoxycytidine. Show that restoration of E-cadherin gene expression correlates with demethylation of 5' regulatory sequences, and reduces the metastatic capability of prostate cancer cells in vivo.